Erythropoietin (EPO) is a glycoprotein hormone that is involved in the maturation and differentiation of erythroblast precursor cells into mature erythrocytes, and is a naturally-occurring monomer polypeptide composed of 165 amino acids (Non-Patent Document 1).
Human EPO is essential for proliferation and differentiation of erythrocytes, and is useful for the treatment of blood diseases characterized by a decrease in erythrocyte production. Clinically, EPO is used for the treatment of anemia, in chronic renal failure (CRF) patients, autologous transfusion and anemia of prematurity, (Non-Patent Documents 2 to 4), as well as in AIDS patients and patients undergoing chemotherapy for cancer (Non-Patent Document 5). In addition, EPO has also been recognized as being effective in chronic anemia.
Although EPO is primarily produced in the kidneys in adults, it is also produced in astrocytes and neurons of the central nervous system, and EPO and EPO receptors have also been discovered in capillaries of the boundary between the brain and the peripheral nervous system. Moreover, systemic administration of EPO has also been reported to reduce the loss of neuron cells in response to cerebral and spinal ischemia, mechanical trauma, epilepsy, excitotoxicity or neuritis by passing through the blood-brain barrier (Non-Patent Documents 6 to 10).
During treatment using proteins in the manner of EPO, problems are encountered such as the short plasma half-life as a result of being susceptible to decomposition by proteases (Non-Patent Documents 11 and 12), and the need to frequently perform intravenous injection in order to maintain an effective therapeutic concentration in the circulation. In addition, although subcutaneous injection may be used as an alternative administration route to intravenous injection, although sustained-release effects are obtained due to the slow rate of absorption from the administration site, plasma concentration is significantly lower than that in the case of intravenous injection. Therefore, the number of injections required to demonstrate an equivalent therapeutic effect is similar to that in the case of intravenous injection, thereby resulting in a burden on patients. In addition, since human serum EPO is a glycoprotein that has a complex sugar chain structure bonded to the surface of the EPO resulting in diverse and wide-ranging glycosylation, it demonstrates an absence of size uniformity, thereby resulting in the problem of recombinant human EPO being unable to be used to produce human serum EPO with good reproducibility.
Thus, there is a need in this technical field for a method and compound, not only EPO having low bioavailability in the treatment of diseases caused by decreased EPO production, including anemia as previously described, but also that increases endogenous EPO.
On the other hand, the amount of EPO produced is known to be controlled according to oxygen concentration through a transcription factor in the form of hypoxia-inducible factor (HIF) (Non-Patent Document 13). Namely, in a normal air atmosphere, although production of EPO is not promoted since an HIF sub-unit (HIF-1α), having a proline residue hydroxylated by 2-oxoglutarate dioxygenase, is decomposed by the ubiquitin proteasome system, under hypoxic conditions, hydroxylation of the proline residue of HIF-1α by 2-oxoglutarate deoxygenase is inhibited, thereby resulting in translocation of the stabilized HIF-1α from the cytoplasm to the nucleus, formation of a dimer with HIF-1β, and promotion of transcription as a result of the dimer bonding to the hypoxia-responsible element (HRE) of the EPO gene, thereby leading to promotion of EPO production.
Enzyme inhibitors of HIF prolyl hydroxylase such as 2-oxoglutarate deoxygenase using this EPO production mechanism have been reported to be used as EPO production promoters (Patent Documents 1 to 4).
However, genes for which expression is controlled by HIF include not only the gene that encodes EPO, but also the gene that encodes vascular endothelial growth factor (VEGF). VEGF has an action that promotes angiogenesis, and has been reported to be able to cause exacerbation of malignant tumors mediated by this function (Non-Patent Documents 14 and 15). In addition, since anemia is also induced by chemotherapy for the treatment of cancer, and anemia drugs can also be considered for administration to cancer patients undergoing such chemotherapy (Non-Patent Document 5), compounds having an action that inhibits the activity of HIF prolyl hydroxylase and have the potential to also promote expression of VEGF and the like that exacerbate cancer also include this risk.
Production of EPO is controlled by a promoter located on the 5′-side of EPO and an enhancer located on the 3′-side, and HIF is thought to promote production of EPO by bonding to an HRE sequence within the enhancer. In addition, GATA-2, NFκB and the like are also known to control EPO production (Non-Patent Documents 16 and 17), and promotion of EPO production is thought to be able to be achieved by a mechanism other than inhibition of the activity of HIF prolyl hydroxylase. On the basis thereof, a compound having an action that promotes EPO production without depending on inhibition of the activity of HIF prolyl hydroxylase is thought to be useful for the treatment of anemia.
In addition, although EPO promotes proliferation and differentiation of erythroblast precursor cells as described above, a compound having an action that promotes maturation and differentiation of erythroblast precursor cells without involving the production of EPO would also be useful as a drug for the treatment of anemia. Although compounds have been reported that have activity that enhances the erythrocyte proliferation promoting action of EPO and have an inhibitory action against hematopoietic cell phosphatase catalyzing dephosphorylation, which is one of the important control mechanisms of EPO signaling (Patent Documents 5 to 7), their activity cannot always be said to be adequate. In addition, although synthetic peptides called hematide have been reported that act on EPO receptors (Non-Patent Document 18), they are required to be administered at a high dosage in order to express activity equivalent to that of EPO, thereby resulting in the problem of being unsuitable for oral administration.
Thus, a low molecular weight drug for the treatment of anemia that enables oral administration and has both EPO production-promoting action and hemoglobin production-promoting action is thought to be useful for treatment of anemia in the future.
On the other hand, although compounds having a fused piperidine backbone relating to the present invention have been disclosed, including a CRTH2 inhibitor effective against inflammatory diseases (Patent Documents 8 and 9), a G protein-coupled receptor inhibitor effective for conditions such as heart failure (Patent Document 10), and a cholesterol transport protein inhibitor effective against diseases such as arteriosclerosis (Patent Documents 11 and 12), none of these publications contains descriptions or suggestions relating to EPO production-promoting action, hemoglobin production-promoting action or treatment of anemia using these compounds.
In addition, Patent Document 13 discloses a cholesterol transport protein inhibitor effective against diseases such as arteriosclerosis represented by the following general formula (a) and the compound of Example 1:
(wherein, R5 and R6, R6 and R7 or R7 and R8 together may form a 4- to 8-membered saturated, partially saturated or unsaturated ring that may be composed of 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom).
In addition, Patent Document 14 discloses a proton pump inhibitor effective against gastric ulcers and the like represented by the following general formula (b) and the compound of Example 5:
(wherein, A and B together may form a CH2—CH2 group, and X represents —NH— or —O—).
In addition, in Non-Patent Document 19, although the following compound (c):
is synthesized based on its interest in terms of organic synthesis chemistry, there is no description relating to its biological activity. However, the compounds described in these publications are different from compounds of the present invention in terms of substituents of tricyclic tetrahydroxyquinoline.
In addition, Patent Document 15 discloses an STAT6 inhibitor effective against inflammatory diseases represented by the following general formula (d):
(wherein, L represents CH2, O or S, n represents 0 or 1, and W, Y and Z may form a methylenedioxy group). However, this publication does not specifically disclose the tricyclic compound of the present invention. Moreover, this publication does not contain any description or suggestion relating to EPO production-promoting action or hemoglobin expression-promoting action.